In 1995 we conducted a cross-sectional study to identify the effects of traditional and western environments on prevalence of type 2 diabetes mellitus (T2DM) and obesity in Pima Indians in Mexico and the United States (1-8). The Mexican Pimas live in a remote mountainous region and at that time had experienced little change from their traditional lifestyle. Nothing was known about their T2DM prevalence. A similar number of non-Pima Mexicans live in the same village. In contrast to the Mexican Pimas, the U.S. Pimas live in more westernized society and are known to have the highest prevalence of diabetes in the world (9). We found that although T2DM and obesity were more prevalent in Mexican Pimas than non- Pimas, both Mexican groups had a significantly lower prevalence of these disorders than U.S. Pimas. The lifestyle of the Mexican population studied included a dramatically higher level of physical activity and a diet higher in fiber and lower in calories derived from fat compared to the U.S. Pimas. Since the U.S. and Mexican Pimas share a similar gene pool we concluded that even in populations genetically prone to T2DM and obesity, their development is determined mostly by environmental circumstances (1). Since 1995 the environmental circumstances of the Mexican Pimas and non-Pimas have changed. The electrical supply to the region has increased, cars have become more prevalent and grocery stores have appeared. The impact of these changes on T2DM and obesity has not been examined. In light of these events, we propose to: 1) compare the current prevalence of T2DM and obesity in Mexican Pimas and non-Pima Mexicans to that present in 1995 with the same measures used previously, including height, weight, waist circumference, body composition, oral glucose tolerance and HbA1c;2) compare current diet, physical activity and total energy expenditure in both Mexican Pimas vs. non-Pima Mexicans using the same methods as the 1995 study to the previous results;3) compare insulin sensitivity between Mexican Pimas and non-Pimas;and 4) document the frequencies of T2DM and obesity-associated genetic variants in Mexican Pimas compared to U.S. Pimas and non-Pima Mexicans. Therefore, we propose to identify genetic and environmental factors and their interactions associated with T2DM and obesity through a 15-year follow-up of the Mexican Pima Indians and non-Pima Mexicans. PUBLIC HEALTH RELEVANCE: Diabetes and obesity have been described as the major public health concerns of the 21st century. The proposed studies will address the means by which genetic predisposition for these two disorders interact with lifestyle to influence disease development.